Metastatic Germ Cell Tumors: Prognosis And Treatment Options

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Introduction

  1. Definition of metastatic germ cell tumours

Germ cell tumours (GCT) can be defined as the non-terminated, continuous cell division primarily occurring in the testis and ovaries, which leads to the formation of cancerous tumours in the reproductive parts of males and females. These types of tumours can also develop in other parts of the body as well. Depending on the location of the GCT, it could be classified into two groups, namely, extragonadal and gonadal. Extragonadal GCT can occur in different regions of the body like lungs, kidneys, abdomen, and in fact, sometimes in the brain too. On the other hand, gonadal GCT only occurs in the gonads of males and females (Testis and ovaries). Further classification of germ cells can be done, and each type will possess unique traits based on which the treatment will vary. The important noticeable point here is, that there are two possibilities in which the GCT could occur. It could either be cancerous (malignant) or non-cancerous (benign). Malignant GCTs can be fatal if the detection and handling of the disease have been neglected for a prolonged time, as these can migrate to external organs. 

GCTs are referred to as Metastatic Germ Cell Tumors (mGCTs) when the gonadal GCT has migrated from its primary location, i.e., testes or ovaries, to the other parts of the body like lungs, bones, lymph nodes, liver, and brain where GCTs metastasize the most frequently. Nonseminoma and Seminoma are the two basic classifications of Metastatic Germ cell tumours. Seminomas are a particular kind of GCT that responds better to chemotherapy and radiation therapy as compared to nonseminomas, which are more truculent and mostly respond to in-depth treatment. 

  1. Importance of prognosis and treatment options:

The right prognosis after the diagnosis of GCT is essential and one of the crucial steps as it leads to the decision about the subsequent treatment of the disease. Depending on the size and location of the tumour, different types of treatment, like radiation therapy, surgery, and chemotherapy, are frequently used for the treatment of mGCT. Depending on the particular type of tumour and its stage, numerous other combinations of medication might be utilised with chemotherapy as it is the fundamental component of therapy. 

Biomarkers or biological markers are quantifiable indications of a biological reaction or circumstances that exist within an organism. There are numerous biomarkers used for the early identification and detection of the disease, such as blood glucose, which acts as a biomarker for detecting diabetes, cholesterol for cardiovascular disease, and tumour markers for the detection and progression of cancer. Therefore, certain guidelines propose measurements of tumour markers HCG, LDH, and AFP before and after the surgical procedure, in addition to the clinical examination and ultrasound of metastatic GCT.

Owing to advancements in medicine, the likelihood of recovery for mGCT has greatly improved over time. Most patients with mGCT are curable, especially with early detection and adequate treatment. The amount of tumour growth, the responsiveness to the medical treatment, and the patient’s general condition are some of the variables that can affect the prognosis. 

Prognosis

Factors affecting prognosis

There are many factors that affect the prognosis of the metastatic germ cell tumour, like histology, the magnitude of metastatic cancer, tumour markers, the Impact of chemotherapy, surgical procedure, different characteristics of each patient, and treatment breakthroughs. 

  • Histology: Histology is essential for making diagnoses and forecasting results. When compared to mixed or non-seminoma tumours of comparable severity, pure seminoma tumours had higher rates of remission and improved survival prospects. Poor prognosis is indicated by primary mediastinal tumours in non-seminomas. There is an ongoing discussion on the predictive value of mediastinal tumours in seminomas and other extragonadal manifestations
  • Magnitude of metastatic cancer: Another important factor that can affect the prognosis of metastatic germ cell tumors is the magnitude of metastatic cancer. The prognosis can be affected by the degree or progress of the metastatic disease, especially whether lymph nodes or other external organs are involved. The prognosis could be worse and the difficulty level during the therapy could also increase depending on the extensiveness of the metastasis
  • Tumour marker: When determining the prognosis of GCT, tumour markers are crucial. Measurements of AFP, LDH, and HCG are frequently used to track the development of disease. These biomarkers' elevated levels suggest a more aggressive tumour and may affect prognosis
  • Impact of chemotherapy: The success of the surgical intervention and the tumour's reaction to the chemotherapy determine the prognosis of GCT. Chemotherapy has a chance of working, but the degree of tumour shrinking or full recovery determines the final result. The prognosis is improved by surgical elimination of the tumour, especially metastatic tumours. For best results, a surgical excision must be performed properly

The prognosis can also be affected by numerous unique characteristics of the patient, including age, general health, and concurrent medical conditions. Younger patients have an enhanced prognosis as compared to older patients. The outcome could potentially be influenced by additional variables, like the existence of specific genetic anomalies. Over the past few years, improvements in treatment approaches, such as enhanced regimens of chemotherapy and surgical methods, have led to better results and prognoses for malignant GCT.

Prognostic classification systems

For metastatic GCT, there are several prognostic categorisation systems that can be used to forecast patient outcomes and direct therapy choices. The following list includes various popular prognostic categorization schemes for metastatic GCT:

  • Categorization by the International Germ Cell Cancer Collaborative Group (IGCCCG): The commonly used IGCCCG classification takes into account several variables, such as tumor marker concentrations, which include AFP and HCG, site of metastatic disease such as lung, liver, or other places, and the existence of non-pulmonary subcutaneous metastasis. It divides patients into favorable, intermediate, or bad prognosis groups, offering recommendations for treatment plans and forecasting survival rates
  • The Indiana University (IU) classification also takes into account the main tumour site (extragonadal or gonadal), the histology, and whether or not there are brain or liver metastases. It classifies patients into groups with excellent, intermediary, or bad prognosis
  • Classification of the Memorial Sloan Kettering Cancer Centre (MSKCC): The MSKCC classification also takes into account the existence or nonexistence of brain or liver metastases, the initial tumour histology (non-seminoma or seminoma), the location of the primary tumour (extragonadal or testicular), tumor markers (LDH, AFP and HCG), and the primary tumour site. It offers risk classification into categories with excellent, middling, or bad prognosis
  • Classification by the German Testicular Cancer Study Group (GTCSG): The initial tumour's histology, the location of the fundamental tumour, the existence or nonexistence of liver or brain metastases, and tumour markers (AFP, HCG, and LDH) are all taken into account by the GTCSG categorization system. It divides patients into groups with favorable, fair, or bad prognoses

Treatment options

Chemotherapy

Chemotherapy is a form of medical treatment in which medications are used to either kill or stop the proliferation of cancer cells. As an integrated treatment, it moves throughout the body to hunt down cancerous cells present in different parts of the body. 

Chemotherapy medications inhibit the capacity of cancer cells to divide and grow, which is how they function. They can either kill cancer cells directly, which is termed cytotoxic chemotherapy or target them specifically to prevent their development and multiplication, which is typically known as targeted therapy. Chemotherapy can be given orally as pills, or intravenously as an injection.

Because cancerous cells and healthy, normal cells might be impacted by chemotherapy, there may be side effects. Fatigue, nausea, vomiting, hair loss, lowered red blood cell numbers, and a higher vulnerability to infections are typical adverse effects. However, not everyone has adverse reactions, and their intensity can differ.

Surgical interventions

Radiotherapy

High-energy radiation is used in radiotherapy to treat tumours and kill cancer cells in particular body parts. Both alone and in conjunction with other treatments are acceptable uses. The intention is to harm the DNA of cancer cells and stop their development and spread. Skin changes and brief tissue inflammation are possible side effects. However, they usually go away following treatment.

Traditionally, radiation therapy (RT) has not been considered a curative option for non-seminomatous germ cell tumours (NSGCT), which are thought to be radio-resistant diseases. Increased doses of RT are necessary to manage NSGCT because they are less radiosensitive than pure seminomas to standard RT doses. This may help illuminate why, since the advent of efficient chemotherapy at the beginning of the 1980s, RT has not played a significant role in the management of nonseminomas. However, case studies examining the implementation of radiation therapy in this situation are frequently out of date, and there isn't any prospective ongoing research examining innovative radiotherapeutic strategies for NSGCT.

High dose chemotherapy with stem cell transplant

A specialized kind of treatment called high-dose chemotherapy with stem cell transplant involves administering large doses of chemotherapy medications accompanied by the transplantation of stem cells in certain cancer instances or other disorders. The procedure of the above-mentioned process is followed by a collection of stem cells, elevated doses of chemotherapy, and finally, the transplantation of stem cells. 

Through a process known as apheresis, stem cells are extracted from either the patient or a donor as part of the operation. For later usage, these stem cells have been frozen. High-dose chemotherapy is applied as the second step to completely eradicate cancer cells. Finally, the patient's blood is re-infused with the frozen stem cells, triggering hematopoietic regeneration and the production of fresh blood cells in the bone marrow.

A study conducted by Ozaydin et al. (2021), deals with the study of high-dose chemotherapy with rescue via stem cell transplantation. This study limelights about High-dose chemotherapy as the first line of treatment for those at low risk, high-dose chemotherapy as a last resort for persistent germ cell tumours, High-dose chemotherapy as a last resort following second-line medication and, chemotherapy at high doses for extragonadal germ cell tumours. Therefore, the study revealed that the National Comprehensive Cancer Network recommends that patients with recurrent or refractory illness only get high-dose chemotherapy with stem cell transplant. It also concluded that according to current EBMT guidelines and recommendations, high-dose chemotherapy with stem cell transplantation continues to be an accepted treatment option for patients with third-line refractory cancer while remaining an experimental option for patients with recurred chemotherapy-sensitive germ cell tumors after a careful analysis of risk and benefits. 

Targeted therapies and immunotherapy

Two separate methods of treatment for cancer that have revolutionized cancer care recently are targeted medicines and immunotherapy. 

Drugs that selectively target certain chemicals or processes involved in the survival and proliferation of cancer cells are known as targeted therapies. Targeted therapies seek to specifically target cancer cells while minimizing damage to healthy cells, in contrast to conventional chemotherapy, which targets both diseased and healthy cells.

Immunotherapy, on the other hand, is a therapeutic strategy that makes use of the immune system to identify and combat cancer cells. It functions by boosting or modifying the immune response such that cancer cells are selectively recognised and destroyed.

According to research conducted by Kenjiro Namikawa and Naoya Yamazaki (2019), Specialized treatment plans for various melanoma subtypes should be developed in the future, taking into account the variations in genetic origins and the therapeutic effectiveness of immunotherapy. 

Management of specific metastatic sites

Brain metastasis

When cancer cells travel through the bloodstream from the main tumour to the brain, this is known as brain metastasis. It is frequent in melanoma, lung cancer, and breast cancer and is linked to challenging treatment options and a bad prognosis. Due to its specific cell types, morphology, metabolism, and immunological conditions, the brain's particular microenvironment influences the progression of metastatic disease and therapy outcomes.

To fill the unmet clinical need, research into brain metastases may help develop fresh therapeutic targets and treatment modalities. Furthermore, such initiatives might shed light on the molecular makeup associated with primary tumours in the brain, which share some difficulties with extracranial cerebral metastases and vice versa. Such research, however, has been severely constrained by the lack of reliable preclinical instances of brain metastasis, highlighting the significance of creating better experimental models that comprehensively account for the metastatic pathway and/or brain microenvironment. 

Lung metastasis

The invasion of cancer cells to the lungs from another primary tumour site is referred to as lung metastasis. It happens when cancer cells separate from the initial tumour and move via the lymphatic or circulatory systems until they reach the lungs, where they grow new tumours. Kidney cancer, prostate cancer, breast cancer, and colon cancer are the most prevalent cancers that can spread to the lungs. However, almost all cancers have the potential to advance to the lungs.

Concerning the dimensions and placement of the secondary tumours, the indications of pulmonary metastasis can change. Typical signs could include alterations in a continual cough, respiratory problems, aches in the chest, exhaustion, loss of weight without cause, and respiratory illnesses that recur.

The underlying cancer type, the degree of the metastasis, the patient's general condition, and their treatment objectives all influence the therapy options for lung metastasis.

According to a study of molecular and cellular agents that can cause lung metastasis by Cucanic et al. (2022), addressing the processes governing the interaction amongst the host microenvironment, immunology, and pulmonary structures that promote metastasis may reveal anticipatory, prognostic, and diagnostic markers that might be targeted to lessen the burden of disease from metastatic spread.

Liver and bone metastasis

The invasion of cancer cells to the liver from another initial tumour site is referred to as liver metastasis. It happens when cancerous cells separate from the original tumour and travel via the lymphatic or circulatory systems before arriving at the liver and developing additional tumours. Tumour implantation in the liver, an extremely metastasis-permissive organ, typically portends death. The liver may perform a variety of specialized tasks according to its specific architecture and cellular make-up, but due to its peculiar biology, particularly its hemodynamic properties and distinctive microenvironment, the liver is inherently friendly to dispersed tumour cells. 

Whenever malignant tumour cells from an initial tumour move to the bones, this is known as bone metastasis. It frequently occurs in cancers that are in an advanced stage. Prostate cancer, breast cancer, and lung cancer, some of the most prevalent cancers in people, all frequently spread to the bone. The reverse direction interactions between tumour cells and bone-forming cells provide the growth of the tumour an exclusive benefit and can result in the degradation of bone or the formation of a new bone matrix. 

Retroperitoneal lymph node involvement

Follow up and surveillance

Importance of regular follow-up visits

For those who have any type of cancer, malignancies, or tumours; be it benign or malignant, routine follow-up visits are essential because they allow for continued surveillance, early identification of any possibility of recurrence of metastasis, and immediate treatment. During these visits, medical personnel can evaluate the patient's mental and physical condition, evaluate treatment results, request pertinent diagnostics and tests, handle any adverse reactions or difficulties, and offer the support and direction that are required. Regular follow-up visits enable prompt interventions and modifications to the therapy regimen based on the patient's changing needs and condition, helping maintain consistency of care, optimize treatment techniques, and enhance overall outcomes.

Monitoring tumour markers and imaging

An essential part of managing cancer is keeping track of tumor markers and imaging. The existence, advancement, or outcome of therapy for some malignancies can be determined by the presence of tumor markers, such as particular proteins or chemicals in the blood. The detection of any alterations that can point to tumor development, recurrence, or the efficacy of treatment is made easier by regular monitoring of tumor markers. Imaging procedures like CT scans, MRIs, or PET scans offer a detailed visualization of the tumor and its surrounding tissues, assisting in the diagnosis of metastasis, gauging the effectiveness of treatment, and assisting in the direction of treatment decisions. These monitoring tools aid medical practitioners in making well-informed choices regarding therapy modifications, follow-up schedules, and general cancer treatment planning.

Late effects and long term survivorship care

Late effects are issues that may develop physically, psychologically, or socially over some time after cancer therapy. These include things like mental distress, cardiovascular troubles, fertility challenges, mental health issues, and persistent pain. These issues are addressed by long-term survivorship care, which also offers continuing surveillance for recurrences of cancer or subsequent cancers and assists survivors in preserving their general health and well-being. Improving the quality lifestyle for survivors of cancer over the long term, includes periodic evaluation appointments, monitoring for severe impacts, promoting health, survival treatment strategies, as well as access to support resources.

Summary

Uncontrolled cell division, particularly within the reproductive organs, characterizes germ cell tumours (GCT), which result in malignant tumours in the reproductive systems. Other body parts may also experience them. Extragonadal GCTs are those that develop outside the gonads, while gonadal GCTs develop inside the gonads. Both benign and malignant GCT are capable of spreading to other organs, with malignant GCT being more likely to do so. Germ cell tumours (GCT) that have metastasized to other areas of the body are known as mGCT. Seminomas respond more effectively to radiation therapy and chemotherapy than nonseminomas, according to a further classification. The characteristics and phase of the tumour determine the likelihood of survival and subsequent therapy. 

In conclusion, effective care for various forms of cancer depends on early detection, correct diagnosis, and individualised treatment programs. The best course of therapy can be chosen with the help of regular tests like mammograms and colonoscopies as well as knowledge of the unique traits of each type of cancer. To improve results and the standard of life for cancer patients, collaboration between healthcare providers and patients is crucial when developing individualized treatment plans.

References

  1. Hahn NM, Sweeney CJ. Germ cell tumors: An update of recent data and review of active protocols in stage I and metastatic disease. Urologic Oncology: Seminars and Original Investigations [Internet]. 2005 Jul [cited 2023 Jun 20];23(4):293–302. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1078143905001018
  2. Beyer J. Prognostic factors in metastatic germ-cell cancer. Andrology. 2019 Jul;7(4):475–8.
  3. Kasai M, Kiyama Y. [Germ cell tumor]. Gan To Kagaku Ryoho. 1995 Oct;22(12):1749–55.
  4. Francolini G, Trodella LE, Marvaso G, Matrone F, Nicosia L, Timon G, et al. Radiotherapy role in non-seminomatous germ cell tumors, radiobiological and technical issues of an unexplored scenario. Int J Clin Oncol [Internet]. 2021 Oct 1 [cited 2023 Jun 21];26(10):1777–83. Available from: https://doi.org/10.1007/s10147-021-01989-7
  5. Ozaydın S, Sahin U, Karadurmus N, Arpaci F, Demirer T. An overview of high dose chemotherapy with autologous stem cell rescue for germ cell tumors in current practice. J BUON. 2017;22(2):306–11.
  6. Namikawa K, Yamazaki N. Targeted therapy and immunotherapy for melanoma in japan. Curr Treat Options Oncol. 2019 Jan 24;20(1):7.
  7. Boire A, Brastianos PK, Garzia L, Valiente M. Brain metastasis. Nat Rev Cancer. 2020 Jan;20(1):4–11.
  8. Cucanic O, Farnsworth RH, Stacker SA. The cellular and molecular mediators of metastasis to the lung. Growth Factors. 2022 Aug;40(3–4):119–52.
  9. Yin JJ, Pollock CB, Kelly K. Mechanisms of cancer metastasis to the bone. Cell Res. 2005 Jan;15(1):57–62.
  10. Clark AM, Ma B, Taylor DL, Griffith L, Wells A. Liver metastases: Microenvironments and ex-vivo models. Exp Biol Med (Maywood). 2016 Sep;241(15):1639–52.

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Manasvi Moudgil

Master’s of Biotechnology - M.Sc. Biotechnology, Coventry University, United Kingdom

Her academic journey has been marked by an unwavering fascination with biotechnology and a genuine passion for scientific exploration. During her studies, she specialised in innovative areas such as gene editing techniques and their applications in healthcare. In addition to her research pursuits, Manasvi actively engages in science communication, sharing her expertise with a wider audience. As she embark on her research career, her ultimate ambition is to become a pioneering figure in scientific research world, motivating and guiding future generations of scientists to push the boundaries of innovation in this field.

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